Traditional classification systems for melanocytic neoplasms rely on clinical and histologic characteristics to describe subtypes of nevi (eg, acquired nevi, congenital nevi, Spitz nevi, blue nevi) and melanomas (eg, superficial spreading melanomas, nodular melanomas, acral lentiginous melanomas, lentigo maligna melanomas). More recently, acquired mutations in oncogenes that lead to constitutive activation of critical signaling pathways have provided additional information useful for classification. These include BRAF
mutations that are frequent in common acquired nevi10
and in melanomas from skin without chronic sun-induced damage8
; KIT mutations in acral and mucosal melanoma and melanomas on skin with chronic sun-induced damage7
mutations in a subset of Spitz nevi3
; and GNAQ
mutations in blue nevi and uveal melanoma.12,13
Integration of underlying genetic aberrations and clinicopathologic features can lead to refined ways to classify melanocytic neoplasms and improve clinical relevance by incorporating information that can guide selection of targeted therapeutic agents.14
Here, we shed further light on the heterogenous group of ASTs by demonstrating that they appear to be composed of biologically distinct entities. In the present study, we have identified a histologically distinct subset of ASTs characterized by BRAFV600E mutations and loss of BAP1 expression. In all cases, BAP1 loss was somatically acquired without evidence of a preexisting germline mutation. These results demonstrate that melanocytic neoplasms with BAP1 alterations can occur outside of the previously described tumor predisposition syndrome caused by germline BAP1 mutations. We have also shown that BAP1 status can be reliably identified by IHC, which will make BAP1 IHC a useful tool for subtyping melanocytic neoplasms. Our observation that a greater number of tumors exhibited loss of BAP1 protein expression by IHC compared with BAP1 deletions or mutations indicates that BAP1 may become functionally inactivated by mechanisms other than deletions or mutations in the coding region; for example, epigenetic changes leading to silencing of the BAP1 gene or other, yet to be identified, alterations that prevent BAP1 expression. Detailed in vitro and in vivo studies are needed to investigate the correlation between nuclear BAP1 protein expression (assessed by IHC) and BAP1 functional activity.
The sporadic BRAFV600E
tumors exhibited a typical epithelioid histomorphology that was previously seen in the BAP1-negative melanocytic skin tumors in patients with BAP1
The cytologic appearances of BRAFV600E
tumors (plump epithelioid cells with amphophilic cytoplasm and very well-demarcated cytoplasmic borders, moderately pleomorphic round/oval nuclei with vesicular chromatin and variably conspicuous nucleoli, and multinucleate/giant cells) were distinctive but were not absolutely specific, as some features were also identified to varying degrees in some BAP1-positive tumors. Similarly, architectural features and stromal alterations absolutely specific to BAP1-negative tumors were not identified. TILs were prominent in many BAP1-negative tumors, but this was also not a specific diagnostic feature.
We previously reported that another subset of ASTs is characterized by HRAS
mutations, copy number increases of chromosome 11p, and distinct microscopic features.3,11
These tumors had similar cytologic features to those described here and were also predominantly intradermal. In contrast to the BRAFV600E
tumors, the HRAS
mutant neoplasms were associated with marked desmoplasia and did not show densely cellular aggregates. These results indicate that BRAFV600E
mutations and loss of BAP1 defines an additional genetic/morphologic subset of epithelioid ASTs (8/32, 25%). Thus, to date, spitzoid tumors are composed of 3 distinguishable categories, HRAS
tumors, and a (probably still heterogeneous) category of tumors with as yet unknown genetic characteristics.
Unfortunately, we did not have follow-up information on the tumors analyzed in our study; hence, we cannot address the important question of whether BAP1
status provides any prognostic information about the tumors. In our experience, patients with ASTs almost invariably have an uneventful follow-up.4
Only a small minority develop widespread metastasis, raising the possibility that they were melanoma from the outset. Future studies are necessary to determine which, if any, genetic or morphologic criteria identified in this study can help in the risk assessment of these tumors.
In conclusion, we have described a distinct subset of ASTs characterized by loss of BAP1 expression, BRAFV600E mutations, and some distinct histologic features. Our findings establish a platform for future studies to investigate the prognostic significance of genetically defined subsets of ASTs.